Receptor Specific Retinoids Probes to Study the Brain Damage Caused byDevelopmental Alcohol Exposure

摘要 怀孕期间摄入酒精会对胎儿造成各种急性和长期的不良影响， 导致后代的胎儿酒精谱系障碍（FASD）。特别是，发育中的大脑对 酒精中毒和认知功能障碍，如学习和记忆，可以在FASD中看到 患者虽然许多因素可能与发育中大脑的酒精毒性有关，但视黄酸（RA） 信号通路通常与酒精中毒的过程有关，因为RA（维生素A的活性形式） A）通过核RA受体调节转录和翻译，其在细胞核中起重要作用。 胚胎及其中枢神经系统的发育，酒精已被证明会干扰类维生素A（与 维生素A）代谢。虽然精确控制RA在胚胎细胞群中的分布似乎是 在中枢神经系统中，过量或缺乏RA已被证明会干扰大脑发育，酒精 通过几种机制干扰类维生素A代谢，导致RA的激活或失活 信号通路因此，RA信号通路可以作为开发治疗药物的靶点。 酒精对大脑发育的毒性。这项转化研究提案旨在确定 实验室合成的新型类维生素A衍生物（RA受体激动剂和拮抗剂）的给药 Bhaskar Das博士（PI，西奈山伊坎医学院）的研究证实了产前或新生儿酒精诱导的 急性神经变性以及神经发生、神经解剖学和行为的长期异常， 在Dr. Mariko Saito（Co-PI，Nathan Kline Research Institute）的实验室中使用FASD小鼠模型。的 该项目的具体目标是：目标。1：从我们的先导分子合成额外的新型维甲酸， 完全表征了特异性和生物活性（Das博士的小组;参见NatureChemicalBiology 2013 PMID： 23584676，PLos One 2011 PMID：22125642和PLos One 2010 PMID：20368991）。然后我们会把 合成其它化合物的方法，所述化合物对蛋白酶裂解更有抗性，更有效， 对受体更有特异性在具体目标2中，我们将确定RA受体激动剂或拮抗剂是否能预防 早期酒精诱导的细胞存活、神经发生、神经解剖学和行为异常。酒精， 或不含RA衍生物，将在妊娠第8天（GD 8）（妊娠早期模型）注射到母鼠中，或在妊娠第8天（GD 8）（妊娠早期模型）注射到幼仔中。 出生后第7天（P7）（妊娠晚期模型），我们将评估RA衍生物是否减弱酒精诱导的 急性神经变性和神经发生、GABA能细胞密度的长期异常， 行为（自发活动和情境恐惧条件反射）。成功完成此翻译 研究计划将有助于确定目标类维生素A衍生物开发用于治疗FASD。

ABSTRACT Alcohol intake during pregnancy causes wide varieties of acute and long-lasting adverse effects on fetuses, resulting in fetal alcohol spectrum disorders (FASD) in offspring. Especially, the developing brain is sensitive to alcohol toxicity, and impairments in cognitive functions, such as learning and memory, can be seen in FASD patients. While many factors may be involved in alcohol toxicity in the developing brain, the retinoic acid (RA) signaling pathway is often implicated in the process of alcohol toxicity, because RA (the active form of vitamin A) that regulates transcription and translation via nuclear RA receptors plays an important role in the development of embryos and their CNS, and alcohol has been shown to disturb retinoid (compounds related to vitamin A) metabolism. While precise control of RA distribution within embryonic cell populations seems to be necessary, and the excess or depletion of RA in the CNS has been shown to disturb brain development, alcohol interferes with retinoid metabolism by several mechanisms, resulting in activation or inactivation of the RA signaling pathway. Therefore, the RA signaling pathway may serve as a target for developing therapeutic applications in alcohol toxicity in the developing brain. This translational research proposal aims to determine if administration of novel retinoid derivatives (RA receptor agonists and antagonists) synthesized in the laboratory of Dr. Bhaskar Das (PI, Icahn School of Medicine at Mount Sinai) alleviates prenatal or neonatal alcohol-induced acute neurodegeneration as well as long-lasting abnormalities in neurogenesis, neuroanatomy, and behavior, using mouse models of FASD in the laboratory of Dr. Mariko Saito (Co-PI, Nathan Kline Research Institute). The specific aims of this project are: Aim. 1: To synthesize additional novel retinoids from our lead molecules that are fully characterized for specificity and bioactivity (Dr. Das’ s group; see Nature Chemical Biology 2013 PMID: 23584676, PLos One 2011 PMID:22125642 and PLos One 2010 PMID: 20368991). Then we will iterate the process to synthesize additional compounds, which are more resistant to protease cleavage, more potent, and more specific to receptors. In the specific Aim 2, we will determine if RA receptor agonists or antagonists prevent early alcohol-induced abnormalities in cell survival, neurogenesis, neuroanatomy and behaviors. Alcohol, with or without RA derivatives, will be injected into dams at gestational day 8 (GD8) (1st trimester model) or pups at postnatal day 7 (P7) (3rd trimester model), and we will assess whether RA derivatives attenuate alcohol-induced acute neurodegeneration and long-lasting abnormalities in neurogenesis, GABAergic cell densities, and behaviors (locomotor activity and contextual fear conditioning). Successful completion of this translational research program will help identify target retinoid derivatives to be developed for the treatment for FASD.